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Pediatric Dosing Going Beyond Milligrams per Kilogram

Andrew Porterfield has a master’s degree in biotechnology management from the University of Maryland and has worked as a marketing communications consultant for many biotechnology and pharmaceutical firms.

It was an unprecedented move: U.S. Health and Human Services Secretary Kathleen Sibelius overruled the FDA when she announced that Teva Pharmaceutical’s Plan B One Step contraceptive pill would not be available to women under 17 years of age. While many observers accused Sibelius of political motivations, the action underscored a far deeper problem for the pharmaceutical industry—how to develop safe and effective therapies for children.

Sibelius claimed that Teva’s study did not adequately address effects on girls as young as 11 (Teva’s study included three 11-year-olds, 35 children who were 14 years old, and 100 who were 15). Three people might be enough of a cohort in an adult trial, but probably wouldn’t address the wide variety of childhood development, one of the many issues with pediatric dosing.

Traditionally, pediatric dosing was calculated using milligrams (or grams) of drug versus kilograms of body weight (body surface areas have been used, too). But the pharmacokinetics of childhood is much more complicated than that, and researchers have bemoaned the lack of pediatric pharmacokinetic studies that could help develop safe, effective medications: only 10 percent of licensed therapeutics have been tested specifically for children.

A recent paper by Ryan Funk and colleagues in Pediatric Clinics of North America points to several factors that make pediatric dosing a scientific challenge:

Shortly after birth, stomach acid levels are relatively low and start to build, which can decrease or delay drug absorption.

Bile salt concentrations in infants are also much lower, which can alter absorption of certain drugs.

Serum penicillin levels drop drastically as a child develops into a teenager (though absorption appears to normalize after four hours in toddlers and older children)

The FDA also has pointed to other areas of variation during development that affect dosing: drugs are eliminated more quickly in younger patients, and changes during maturation have significant—and largely unknown—effects on distribution and metabolism.

Thanks to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Trials Network (a collaboration of NIH, the BPCA program, and Duke University, the number of clinical trials focusing on childhood dosing has risen: currently 350 trials involve dosing to children. The network is coordinating clinical trials as well as translational research that would result in more reliable methods to predict and analyze the effects of new medications on the 80 million U.S. children and 1.7 billion worldwide.

Armed with such valuable information, the industry (and perhaps FDA) can more confidently replace accusations of politics with solid science.